The prostate-specific antigen (PSA) as a biomarker for prostate cancer (PCa) diagnosis has been widely used in the clinic for several decades. However, PSA has a low specificity for PCa diagnosis, thereby several genes, blood, and urine-based biomarkers (such as sarcosine) underlying biology of PCa progression are being developed to improve the accuracy of PCa diagnosis. In the present review, we focus on novel PCa biomarkers, which are potentially superior to PSA in PCa screening and facilitate clinical PCa diagnosis. The early PCa screening with reliable biomarkers is critical in reducing the mortality of clinical PCa (high-risk PCa). For clinical insignificant PCa (low-risk PCa) patients and benign prostatic hyperplasia patients, biopsies should be avoided and disease progression should be monitored using non-invasive biomarkers.